It is known to label an antibody with a metal atom, in order to target the metal atom to a specific tissue type, both in vitro and in vivo. Such labelled antibodies have applications in locating specific tissue types (e.g. employing computer-aided tomographic techniques where the metal atom is in some way detectable) and in the treatment of cell disorders (e.g. treating mammalian tumours where the metal atom is a cytotoxic radionucleide).
Conventionally, the metal atom has been complexed to a conjugate compound comprising a ligand covalently attached to an antibody. The ligand may be, for example, an acyclic chelate such as a substituted diethylenetriaminepentaacetic acid (DTPA) (Gansow O. A. et al, Inorg. Chem., (1986), 25, 2772) or ethylenediaminetetraacetic acid (EDTA) (Meares, C. F. et al, Acc. Chem. Res., (1984), 17, 202). Such acylic complexes however tend to be unstable in vivo either as a result of acid-catalysed decomplexation or competitive chelate binding by Ca.sup.2+ or Zn.sup.2+ in serum or as a result of competition from transferrin (Moerlein, S. M. et al, Int. J. Nuc. Med. Biol., (1981), 8, 277). The lack of stability can result in uncomplexed metal atoms in the body which have a cytotoxic effect on healthy tissue or which markedly reduce the signal-to-noise ratio of an imaging technique. The use of macrocyclic ligands in the labelling of antibodies has been suggested in broad terms (Gansow, O. A. et al, Am. Chem. Soc. Symp. Ser., (1984), 241, 215; Published British patent application GB2122641A; Meares, C. F. et al, Anal. Biochem., (1985), 148, 249-253)).
The object of the present invention is to provide improved conjugate compounds involving macrocyclic ligands capable of binding metals to give complexes which are stable, in vivo.